Cyclic guanosine monophosphate as a mediator of vasodilation.

Abstract

Although cyclic guanosine monophosphate (GMP)' was first described in biological samples more than two decades ago, its role in some physiological processes has only become apparent in the past few years (see references [1][2][3][4]. This relatively slow development is probably attributable to the low concentrations of the nucleotide in tissues, the complex and insensitive methods available during the early studies, and the biases many investigators had regarding its possible functions. The latter was undoubtedly influenced by the many similarities of the cyclic GMP system with that of cyclic AMP and the attention cyclic AMP has received during this period. While analogies and similarities between these two cyclic nucleotide systems do exist, the cyclic GMP system presents more complexities due to the existence of several isoenzymes responsible for its synthesis.It is known that the conversion of guanosine triphosphate (GTP) to cyclic GMP is catalyzed by at least two isoenzyme forms of guanylate cyclase. The kinetic, physicochemical, and antigenic properties of the cytosolic and membrane-associated isoenzymes are quite different (see references 2, 4). The relative abundance of the soluble and particulate enzyme is variable in different tissues and species. While intestinal mucosa and retina possess predominately the particulate isoenzyme and platelets contain the soluble isoenzyme, most tissues such as vascular smooth muscle have both isoenzymes. Furthermore, the regulation of each of these isoenzymes is quite different. The soluble enzyme appears unique in that it can be activated by reactive free radicals such as nitric oxide (5), and probably hydroxyl free radical (6) and some porphyrins (7,8). On the other hand, the particulate isoenzyme can be activated with agents such as Escherichia coli heat-stable enterotoxin (9-1 1), atriopeptins (12, 13), and hemin (14). Cations, thiols, other redox agents, and detergents also have complex effects on the activity of both isoenzymes (2).Studies with the kinetic characterization of these isoenzymes led to the present understanding of the role of cyclic GMP in smooth muscle relaxation. Azide, added to inhibit GTPase activity in crude enzyme preparations, was found to activate the enzyme (15). While some hormones, autocoids, and other agents were able to increase cyclic GMP accumulation in intact tissues, these agents had no effects on guanylate cyclase activity in broken Receivedfor publication 9 January 1986.1. Abbreviations used in this paper: EDRF, endothelial-derived relaxant factor; GMP, guanosine monophosphate; GTP, guanosine triphosphate; ST, Escherichia coli heat-stable enterotoxin. cell preparations. It was reasoned that an understanding ofazide activation of guanylate cyclase could lead to understanding the mechanisms of hormonal regulation of the enzyme and some functions of cyclic GMP. Some of these predictions have been fulfilled. The stimulatory effects of azide were dependent upon the presence of heme-containing proteins in guanylate cyclase incubations s...

A dicarba analog of β‐atrial natriuretic peptide (β‐ANP) inhibits guanosine 3′,5′‐cyclic monophosphate production induced by α‐ANP in cultured rat vascular smooth muscle cells

“…It is generally accepted that cGMP mediates vascular smooth muscle relaxation evoked by CY-ANP [14]. cu-ANP has specific receptors on cultured rat VSMC and is known to stimulate intracellular guanylate cyclase [9].…”

“…In spite of this considerable binding to cells, analog III did not stimulate cGMP production in VSMC even at 10m5 M, while cu-ANP exhibited remarkable stimulation with an EDso value of 3 x lo-* M ( fig.3). These results suggest that analog III is either a competitive antagonist of cu-ANP or a socalled clearance receptor (C-receptor) agonist, which is able to bind to the C-receptor but not to the bioactive receptor (B-receptor), only the Breceptor being coupled to guanylate cyclase [14,15]. We therefore examined analog III with special reference to its effect on the a-ANPinduced production of intracellular cGMP in VSMC.…”

The effects of nitric oxide on the immune system during Trypanosoma cruzi infection

“…The biological importance of this ubiquitous intra-and intercellular signalling molecule was first described in the early 1980s as being part of the endothelial derived relaxing factors (Furchgott & Zawadzki 1980). NO was named "Molecule of the Year" in 1992 by the journal Science and, later that decade, studies were conducted to demonstrate its cardinal mechaits cardinal mechanism of action on vascular smooth muscle cells (Murad 1986). These studies made it clear that generation of NO by endothelial cells causes smooth muscle relaxation through activation of guanylate cyclase by nitrosation of its heme group.…”

Inhaled nitric oxide in term and preterm infants

“…Further studies revealed that NO is released from the vascular endothelium when L-argenine is converted to L-citruline and that the reaction is facilitated by the enzyme NO synthase (NOS). [2][3][4] Nitric oxide contributes to the relaxation of smooth muscle via the following mechanism. The stimulation of NOS activity increases the release of NO, which then diffuses in to the adjacent smooth muscle cell and binds to the heme moiety of cytosolic guanylate cyclase.…”

“…Activation of guanylate cyclase increases the intracellular concentration of cyclic guanosine monophosphate, resulting in relaxation of the smooth muscle. 4 Once released, NO is quickly inactivated by combining with hemoglobin to produce methemoglobin and eventually forming inorganic nitrate and nitrites 5 ( Figure 1). …”